Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA‐transcriptome homeostasis: a genomics perspective

In this review, we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, amyotrophic lateral sclerosis, and spinal muscular atrophy. We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP‐43, FUS, SMN, and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration. We review reported functional and physical interactions between these four proteins, highlighting their common association with nuclear bodies and small nuclear ribonucleoprotein particle biogenesis and function. We discuss how these interactions are turning out to be particularly relevant for the control of transcription and chromatin homeostasis, including the recent identification of an association between SMN and Senataxin required to ensure the resolution of DNA‐RNA hybrid formation and proper termination by RNA polymerase II. These connections strongly support the existence of common pathways underlying the spinal muscular atrophy and amyotrophic lateral sclerosis phenotype. We also discuss the potential of genome‐wide expression profiling, in particular RNA sequencing derived data, to contribute to unravelling the underlying mechanisms. We provide a review of publicly available datasets that have addressed both diseases using these approaches, and highlight the value of investing in cross‐disease studies to promote our understanding of the pathways leading to neurodegeneration. Emerging intricate connections between four multifunctional proteins involved in RNA metabolism with a causal role in Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy – TDP‐43, FUS, SMN, and Senataxin – highlight key biomolecular processes underlying these diseases and bring transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration.